Spinocerebellarataxias(SCAs)areneurodegenerativesyndromesofautosomalinheritance.Theyare characterizedbycerebellardysfunctionandmaybeassociatedwithotherneurologicalsignssuchasdystonia andmyoclonus.Nocureiscurrentlyavailableforthesesyndromes,largelybecausewelackadetailed understandingofthecellularmechanismscausingthedisease.TheMoonwalker(MWK)mouseisarodent modelofthehumanspinocerebellarataxia41(SCA41).ItcarriesagainoffunctionmutationoftheTRPC3 channel.CerebellarexpressionofTRPC3ishighlycell-specific,beingpresentonlyinPurkinjecells(PCs)and unipolarbrushcells(UBCs).IntheearlystagesoftheMWKataxiaPCsarefunctionallyimpairedandUBCs arealmostcompletelyablated.Thus,acriticalquestionraisedbytheMWKataxiamodeliswhethereitherthe PCimpairmentortheUBClosscanautonomouslycausethedisease,orwhetheracombinationofthetwois requiredtocausetheataxicphenotype.Toanswerthisquestionitisnecessarytoselectivelyexpressthe MWKmutationinoneandnottheothercelltype.Inordertodoso,weproposetomakeanewCre-dependent TRPC3mwkknock-inmouseline(TRPC3mwkfx)byusingageneticswitch(FLEx)strategy.Wewillbreedthese micewithPC-specificPcp2CremicetoselectivelydriveexpressionTRPC3mwkinPCsandwewillcharacterize themotorphenotypeandthecerebellarpathologyinthePC-specificTRPC3mwkmiceSuccessfulcompletionof theseexperimentswillshedlightonthepathogenicmechanismoftheMWKataxiaandwillallowdissectingthe selectivecontributionofPCimpairment.Thisnewtransgenic(TRPC3mwkfx)mousewillalsobeessentialfor futureexperimentsthatwilltakeadvantageofthismousetoselectivelyexpresstheMWKmutationinUBCs, andinvestigatetheroleoftheseneuronsintheMWKataxiaand,moreingeneral,inthecerebellarnetwork. Additionally,thismouselinemayalsohelpstudyingtheroleofTRPC3inothercellpopulationswherethis channelisexpressed,withinandoutsidetheCNS.
Spinocerebellar ataxias are debilitating neurodegenerative syndromes of genetic origin and the moonwalker (MWK) mouse is a recent model of spinocerebellar ataxia 41, which is caused by a gain of function mutation in TRPC3, an ion channel expressed in cerebellar Purkinje (PCs) and unipolar brush cells (UBCs). The goal of this project is to create a transgenic mouse that selectively expresses the pathogenic MWK mutation in PCs, thus allowing the dissection of the relative importance of PCs and UBCs in the pathogenesis of this ataxia. By providing a deeper understanding of the pathogenic mechanism, our model may help designing more specific therapeutic approaches to ataxias.
